1. Field of the Invention
The present invention relates to a pharmaceutical preparation for therapy of a patient suffering from a symptom caused by acylcarnitine metabolic dysfunction, or for improvement or prophylaxis of such symptom.
2. Description of Related Art
The majority of energy supply for human cells is generated in the mitochondrial glycolysis and fatty acid metabolism. In such energy metabolism, carnitine plays some important roles. That is, although being the major source of the energy supply, a long-chain fatty acid itself can not pass through the inner mitochondrial membrane, and hence free carnitine is required in the transfer of the long-chain fatty acid across the mitochondrial membrane. Further, the free carnitine has another important role. Namely, when a short-chain fatty acid-CoA/CoA ratio is increased by, for example, enhanced glycolysis or heat generation through exercise, the activities of numerous enzymes such as pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase are inhibited, and the free carnitine has a function or activity of inhibiting or suppressing such abnormal increase of the short-chain fatty acid-CoA (coenzyme A) produced by .beta.-oxidation of a fatty acid and of preventing increase of an acetyl-CoA caused by enhanced glycolysis to maintain the short-chain fatty acid-CoA/CoA ratio in a constant range.
Decrease of the free carnitine having such important roles in the energy metabolism is expected to cause cellular dysfunction or cellular abnormality. Indeed, aiming at the functions of free carnitine which does not bond with a fatty acid, it has been reported that primary and/or secondary carnitine deficiency cause a lot of neuro-muscular symptoms. Such carnitine deficiency is defined as a decrease of the intracellular free carnitine level or total carnitine level which is the sum of the free carnitine and acyl-binding carnitines. It has also been reported that administration of free carnitine is a useful treatment to a patient suffering from such symptom.
As mentioned above, the physiological roles of the free carnitine have been well studied in the world and the administration of the free carnitine is clearly established as a treatment for carnitine deficiency. However, as for the acylcarnitine, i.e. a carnitine binding with a fatty acid, most of investigators think that the acylcarnitine might be nothing but a temporary substance in the long-chain fatty acid uptake to the mitochondria. In fact, it is reported that the serum acylcarnitine discharged from mitochondria is excreted to urine, and that reabsorption ratio of the acylcarnitine is lower than that of the free carnitine, and therefore, in the usual state, the free carnitine concentration in serum is several times as high as the acylcarnitine concentration, but in urine, the acylcarnitine concentration is higher than the free carnitine concentration. Accordingly, little attention has been paid to the in vivo physiological and biochemical roles of the serum acylcarnitine itself at present.
In EP-A1-0517125 corresponding to Japanese Patent Application Laid-open No. 155766/1993 (JP-A-5-155766), a pharmaceutical composition containing an acyl-L-carnitine is disclosed. The pharmaceutical composition is, however, used in order to recover the decreased muscular tonus (myotony) of a patient immobilized for a long period because of the fixation of the limbs due to bone fracture. EP-A1-0516594 corresponding to Japanese Patent Application Laid-open No. 148200/1993 (JP-A-5-148200 discloses the use of an acyl-L-carnitine, especially isovaleryl-L-carnitine, as a therapeutic agent only for the treatment of the muscular disturbance (myopathy), degenerative diseases of nerves (for example, Alzheimer's senile dementia and so on) and for the inhibition of proteolysis in liver, skeletal muscle and cardiac muscle. However, the symptoms, to which these therapeutic agents are applied, are quite different from those caused by or related with the metabolic dysfunction of the acylcarnitine.